Abstract
Convection-enhanced delivery (CED) has been introduced as a concept in cancer treatment to generate high local concentrations of anticancer therapeutics and overcome the limited diffusional distribution, e.g., in the brain. RNA interference provides interesting therapeutic options to fight cancer cells but requires nanoparticulate (NP) carriers with a size below 100 nm as well as a low zeta potential for CED application. In this study, we investigated calcium phosphate NPs (CaP-NPs) as siRNA carriers for CED application. Since CaP-NPs tend to aggregate, we introduced a new terpolymer (o14PEGMA(1:1:2.5) NH3) for stabilization of CaP-NPs intended for delivery of siRNA to brain cancer cells. This small terpolymer provides PEG chains for steric stabilization, and a fat alcohol to improve interfacial activity, as well as maleic anhydrides that allow for both labeling and high affinity to Ca(II) in the hydrolyzed state. In a systematic approach, we varied the Ca/P ratio as well as the terpolymer concentration and successfully stabilized NPs with the desired properties. Labeling of the terpolymer with the fluorescent dye Cy5 revealed the terpolymer’s high affinity to CaP. Importantly, we also determined a high efficiency of siRNA binding to the NPs that caused very effective survivin siRNA silencing in F98 rat brain cancer cells. Cytotoxicity investigations with a standard cell line resulted in minor and transient effects; no adverse effects were observed in organotypic brain slice cultures. However, more specific cytotoxicity investigations are required. This study provides a systematic and mechanistic analysis characterizing the effects of the first oligomer of a new class of stabilizers for siRNA-loaded CaP-NPs.
Highlights
In recent decades, nanoparticulate systems have become an important issue as a drug delivery system, especially in cancer treatment [1].One possible strategy to deliver nanotherapeutics is direct infusion of pharmaceuticals in the target tissue via convection-enhanced delivery (CED)
Since calcium phosphate NPs (CaP-NPs) tend to aggregate, we introduced a new terpolymer (o14PEGMA(1:1:2.5) NH3) for stabilization of calcium phosphate (CaP)-NPs intended for delivery of siRNA to brain cancer cells
This study provides a systematic and mechanistic analysis characterizing the effects of the first oligomer of a new class of stabilizers for siRNA-loaded CaP-NPs
Summary
Nanoparticulate systems have become an important issue as a drug delivery system, especially in cancer treatment [1].One possible strategy to deliver nanotherapeutics is direct infusion of pharmaceuticals in the target tissue via convection-enhanced delivery (CED). A promising class of therapeutics for a targeted, localized tumor application is siRNAs, which can decrease the expression of cancer-relevant genes and, in consequence, induce apoptosis in the tumor cells [4,5,6,7]. In contrast to other gene delivery systems, the susceptibility of inorganic CaP to acid environments facilitates dissolution in endosomes and siRNA release into the cytoplasm [17]. This susceptibility limits a potential application in solid tumors, application of siRNA-loaded CaP-NPs after tumor resection might help to inhibit relapse
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